Abstract Pneumonia biology should be the focus of an R35 from the NHLBI. Pneumonia is a leading global burden of disease in every analysis. It kills more children worldwide and hospitalizes more US children than does any other disease. Older adults are even more affected. The incidence and risk of death from pneumonia increase throughout adulthood until becoming orders of magnitude greater than for young children. But the idea that adults have to be old and frail to get pneumonia is a counter-productive misconception. Pneumonia susceptibility is pronounced in middle age, with the median age of non-immunocompromised US adults hospitalized for pneumonia being 57 years. In addition to the directly attributable immediate morbidity and mortality, pneumonia also accelerates unhealthy aging, including exacerbations and more rapid decline of chronic pulmonary diseases, cardiovascular diseases, and more. A wide ranging assortment of viruses, bacteria, and other microbes causes pneumonia, with no one organism responsible for as much as a tenth of cases. It is not about the microbe. These are pathobionts, not pathogens. They circulate among us repeatedly or live on us continuously, growing in the lung to cause pneumonia only under exceptional circumstances. Whether pneumonia ensues depends on the quality and quantity of the host response. Pneumonia results from failures of lung defense more than from microbial virulence. We need to understand the lung defenses that normally prevent pneumonia in young healthy adults before we can identify, prevent, or reverse what goes wrong to make individuals susceptible to pneumonia. Our ongoing research program is addressing the question of lung defense against pneumonia with a long-standing and continuing focus on pulmonary inflammation and innate immunity that is now coupled with a newer emphasis on naturally acquired heterotypic adaptive immunity against respiratory pathobionts. This research program includes 2 ongoing NHLBI R01s that are defining roles of lung epithelial cells and alveolar macrophages in mediating protection against pneumonia. These 2 grants together total 26 R01-years of support from the NHLBI, and we propose unifying these distinct components of our mature and productive research program into a more integrated R35 award. During the coming years, we envision our research program (i) advancing mechanistic understanding of lung defense against pneumonia by functionally integrating the activities of lung constituents and adaptive immunity, (ii) leveraging discoveries in lung defense to generate new approaches to preventing and curing pneumonia, and (iii) forwarding the concept that pneumonia susceptibility is a chronic disease of aging, and attacking the mechanisms of susceptibility rather than (or in addition to) the acute infection has the greatest promise for diminishing the burden of this lung disease.